The Section has focused on defining the role of the central stress response, (hypothalamic pituitary adrenal, HPA, axis) in susceptibility to inflammatory disease and associated behavioral responses to stress. Animal studies analyze the association of differential inflammatory disease susceptibility, behavioral responses to stress and relative HPA axis hypo- and hyperresponsiveness in inflammatory disease susceptible and resistant Lewis (LEW/N) and Fischer (F344/N) rats. Intracerebroventricular (i.c.v.) hypothalamic transplantation and genetic segregation and linkage are used to define the relationship between traits and to identify associated gene loci. Transplantation of F344/N or LEW/N hypothalamic tissue i.c.v. into LEW/N rats is associated with increased host hypothalamic CRH expression and plasma corticosterone responses and decreased peripheral inflammation, but does not affect memory T cells. The uncoupling of these components of inflammation suggests that each may be regulated by different neuronal factors, and that hypothalamic CRH and CNS factors may play a greater role in acute, innate rather than the later memory phase of peripheral inflammatory/ autoimmune responses. In genetic linkage studies in collaboration with Dr. Howard Jacob (Harvard Medical School), we have identified over 400 polymorphic microsatellite loci in LEW/N and F344/N rats. These polymorphic microsatellite loci will be used in the next phase of linkage and segregation studies, to determine which polymorphic loci segregate with HPA axis responsiveness, acoustic startle and carageenan inflammatory response. In human subjects, we have developed an ex vivo assay for glucocorticoid sensitivity: dexamethasone suppression of LPS induced IL-6 responses. With Dr. Philip Gold, we have defined HPA axis responses in inflammatory and fatigue syndromes. In vitro, dexamethasone dose-dependently inhibits LPS induced IL-6 production. In vivo dexamethasone administration suppresses IL-6 production in a dose- dependent fashion. Physiological conditions associated with HPA axis stimulation, such as 30 minutes of exercise at 90% VO2 max, decrease dexamethasone inhibition of IL-6 responses. Patients with multiple sclerosis show heterogeneous glucocorticoid sensitivity suggesting a sub- population of glucocorticoid-resistant m.s. patients. AIDS-related studies have also been initiated of HPA axis responses in a murine model of AIDS, MAIDS (collaborators: Janet Hartley and Herbert Morse, NIAID) and in human subjects (collaborators: Giuseppe Pantaleo and Anthony Fauci, NIAID).